Benzamide modulators of metabotropic glutamate receptors

ABSTRACT

The present invention is directed to compounds which are allosteric modulators of metabotropic glutamate receptors, including the mGluR5 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2004/008627, filed Mar. 22, 2004,which claims priority under 35 U.S.C. §119 from U.S. application Ser.No. 60/457,734, filed Mar. 26, 2003.

BACKGROUND OF THE INVENTION

The excitatory amino acid L-glutamate (sometimes referred to hereinsimply as glutamate) through its many receptors mediates most of theexcitatory neurotransmission within the mammalian central nervous system(CNS). The excitatory amino acids, including glutamate, are of greatphysiological importance, playing a role in a variety of physiologicalprocesses, such as long-term potentiation (learning and memory), thedevelopment of synaptic plasticity, motor control, respiration,cardiovascular regulation, and sensory perception.

Glutamate acts via at least two distinct classes of receptors. One classis composed of the ionotropic glutamate (iGlu) receptors that act asligand-gated ionic channels. Via activation of the iGlu receptors,glutamate is thought to regulate fast neuronal transmission within thesynapse of two connecting neurons in the CNS. The second general type ofreceptor is the G-protein or second messenger-linked “metabotropic”glutamate (mGluR) receptor. Both types of receptors appear not only tomediate normal synaptic transmission along excitatory pathways, but alsoparticipate in the modification of synaptic connections duringdevelopment and throughout life. Schoepp, Bockaert, and Sladeczek,Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, BrainResearch Reviews, 15, 41 (1990).

The present invention relates to allosteric modulators of mGlureceptors, in particular mGluR5 receptors. The mGluR receptors belong tothe Type III G-protein coupled receptor (GPCR) superfamily. Thissuperfamily of GPCR's includes the mGluRs as well as a number of otherreceptors including the calcium-sensing receptors, GABAB receptors andpheromone receptors. The family III GPCRs are unique in that they areactivated by binding of effectors to the amino-terminus portion of thereceptor protein. The mGlu receptors are thought to mediate thedemonstrated ability of glutamate to modulate intracellular signaltransduction pathways. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54,581 (1998). They have been demonstrated to be localized both pre- andpost-synaptically where they can regulate neurotransmitter release,either of glutamate or of other neurotransmitters, or modify thepost-synaptic response of neurotransmitters, respectively.

At present, eight distinct mGlu receptors have been positivelyidentified, cloned, and their sequences reported. These are groupedbased on their amino acid sequence homology, their ability to effectcertain signal transduction mechanisms, and their known pharmacologicalproperties. Ozawa, Kamiya and Tsuzuski, Prog. Neurobio., 54, 581 (1998).For instance, the Group I mGluR receptors, which include the mGluR1 andmGluR5, are known to activate phospholipase C (PLC) via Galphaq-proteinsthereby resulting in the increased hydrolysis of phosphoinositides andintracellular calcium mobilization. Aside from the normal agonistglutamate, several compounds have been reported to activate the Group ImGlu receptors including DHPG, (R/S)-3,5-dihydroxyphenylglycine.Schoepp, Goldworthy, Johnson, Salhoff and Baker, J. Neurochem., 63, 769(1994); Ito, et al., keurorep., 3, 1013 (1992). The Group II mGlureceptors consist of the two distinct receptors, mGluR2 and mGluR3receptors. Both have been found to be negatively coupled to adenylatecyclase via activation of Galphai-protein. These receptors can beactivated by the normal agonist, glutamate, as well as by a selectivecompound such as 1S,2S,SR,6S-2aminobicyclo[3.1.0]hexane-2,6-dicarboxylate. Monn, et al., J. Med.Chem., 40, 528 (1997); Schoepp, et al., Neuropharmacol., 36, 1 (1997).Similarly, the Group III mGlu receptors, including mGluR4, mGluR6,mGluR7 and mGluR8, are negatively coupled to adenylate cyclase via Gaiand, in addition to the normal agonist, glutamate, are potentlyactivated by L-AP4 (L-(+)-2-amino-4-phosphonobutyric acid). Schoepp,Neurochem. Int., 24, 439 (1994).

It has become increasingly clear that there is a link between modulationof excitatory amino acid receptors, including the glutamatergic system,through changes in glutamate release or alteration in postsynapticreceptor activation, and a variety of neurological and psychiatricdisorders. e.g. Monaghan, Bridges and Cotman, Ann. Rev. Pharmacol.Toxicol., 29, 365-402 (1989); Schoepp and Sacann, Neurobio. Aging, 15,261-263 (1994); Meldrum and Garthwaite, Tr. Pharmacol. Sci., 11, 379-387(1990). The medical consequences of such glutamate dysfunction makes theabatement of these neurological processes an important therapeutic goal.

SUMMARY OF THE INVENTION

The present invention is directed to compounds which are potentiators ofmetabotropic glutamate receptors, including the mGluR5 receptor, andwhich are useful in the treatment or prevention of neurological andpsychiatric disorders associated with glutamate dysfunction and diseasesin which metabotropic glutamate receptors are involved. The invention isalso directed to pharmaceutical compositions comprising these compoundsand the use of these compounds and compositions in the prevention ortreatment of such diseases in which metabotropic glutamate receptors areinvolved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   R¹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) halogen,    -   (3) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (4) —OC₁₋₆alkyl,    -   (5) —S(O)_(m)—C₁₋₆alkyl, wherein m is selected from 0, 1 and 2,    -   (6) —CO₂R⁹, wherein R⁹ is independently selected from:        -   (a) hydrogen,        -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (c) benzyl, and        -   (d) phenyl,    -   (7) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selected        from:        -   (a) hydrogen,        -   (b) —C₁₋₆alkyl, which is unsubstituted or substituted with            1-6 fluoro,        -   (c) —C₅₋₆cycloalkyl,        -   (d) benzyl,        -   (e) phenyl,        -   (f) —S(O)₂—C₁₋₆alkyl,        -   (g) —S(O)₂-benzyl, and        -   (h) —S(O)₂-phenyl,    -   (8) —S(O)₂—NR¹⁰R¹¹,    -   (9) phenyl, which is unsubstituted or substituted with one or        more substituents independently selected from:        -   (a) —C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) hydroxy,        -   (e) trifluoromethyl, and        -   (f) —OCF₃;-   R³ is selected from the group consisting of:    -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (2) C₃₋₇cycloalkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (3) phenyl, which is unsubstituted or substituted with one or        more substituents independently selected from:        -   (a) —C₁₋₆alkyl, which is unsubstituted or substituted with            —NR¹⁰R¹¹,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) hydroxy,        -   (e) trifluoromethyl,        -   (f) —OCF₃;        -   (g) —CO₂R⁹,        -   (h) —NR¹⁰R¹¹,        -   (i) —C(O)NR¹⁰R¹¹, and        -   (j) —NO₂,    -   (4) heterocycle, wherein heterocycle is selected from:        -   benzoimidazolyl, benzimidazolonyl, benzofuranyl,            benzofurazanyl, benzopyrazolyl, benzotriazolyl,            benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,            cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl,            indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,            isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl,            oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl,            pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,            pyridazinyl, pyridyl, pyrimidyl, payrolls, quinazolinyl,            quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,            tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,            triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,            piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl,            morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,            dihydrobenzofuranyl, dihydrobenzothiophenyl,            dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl,            dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl,            dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl,            dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,            dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl,            dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl,            dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl,            tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides            thereof, which is unsubstituted or substituted with one or            more substituents independently selected from:        -   (a) —C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) hydroxy,        -   (e) phenyl,        -   (f) trifluoromethyl,        -   (g) —OCF₃;        -   (h) —CO₂R⁹,        -   (i) —NR¹⁰R¹¹, and        -   (j) —CONR¹⁰R¹¹;-   R⁴ is selected from the group consisting of:    -   (1) C₁₋₆alkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl,    -   (2) C₃₋₇cycloalkyl, which is unsubstituted or substituted with        halogen, hydroxyl or phenyl, and    -   (3) phenyl, which is unsubstituted or substituted with one or        more substituents independently selected from:        -   (a) —C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) hydroxy,        -   (e) trifluoromethyl,        -   (f) —OCF₃,        -   (g) —CO₂R⁹,        -   (h) —NR¹⁰R¹¹,        -   (i) —CONR¹⁰R¹¹, and        -   (j) —NO₂;    -   (4) heterocycle, wherein heterocycle is selected from:        -   benzoimidazolyl, benzimidazolonyl, benzofuranyl,            benzofurazanyl, benzopyrazolyl, benzotriazolyl,            benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,            cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl,            indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,            isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl,            oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl,            pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,            pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl,            quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,            tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,            triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,            piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl,            morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,            dihydrobenzofuranyl, dihydrobenzothiophenyl,            dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl,            dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl,            dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl,            dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl,            dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl,            dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl,            dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl,            tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides            thereof, which is unsubstituted or substituted with one or            more substituents independently selected from:        -   (a) —C₁₋₆alkyl,        -   (b) —O—C₁₋₆alkyl,        -   (c) halo,        -   (d) hydroxy,        -   (e) phenyl,        -   (f) trifluoromethyl,        -   (g) —OCF₃,        -   (h) —CO₂R⁹,        -   (i) —NR¹⁰R¹¹, and        -   (j) —CONR¹⁰R¹¹;    -   or wherein R⁴ and R⁵ are joined together to form a phthalimidyl,        succinimidyl or glutamidyl ring, which is unsubstituted or        substituted with one or more substituents independently selected        from the definitions of R¹;-   R⁵ and R⁶ are independently selected from the group consisting of:    -   (1) hydrogen, and    -   (2) C₁₋₆alkyl;-   n is an integer selected from 1, 2 and 3;    and pharmaceutically acceptable salts thereof and individual    diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein

-   R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —O—C₁₋₆alkyl,    -   (4) halo,    -   (5) hydroxy,    -   (6) —NO₂, and    -   (7) phenyl;        and R¹ and R³ are defined herein;        and pharmaceutically acceptable salts thereof and individual        enantiomers and diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R³ is defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein R³ is defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaId:

wherein R¹, R², R⁴ and R⁵ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIe:

wherein R⁴ and R⁵ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIf:

wherein R⁴ and R⁵ are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds wherein R¹ ishydrogen.

An embodiment of the present invention includes compounds wherein R² ishalogen.

An embodiment of the present invention includes compounds wherein R² isfluoro.

An embodiment of the present invention includes compounds wherein R² ischloro.

An embodiment of the present invention includes compounds wherein R² isbromo.

An embodiment of the present invention includes compounds wherein R² ismethyl.

An embodiment of the present invention includes compounds wherein R³ isphenyl, which is unsubstituted or substituted with one or moresubstituents independently selected from:

-   -   (a) —C₁₋₆alkyl,    -   (b) —O—C₁₋₆alkyl,    -   (c) halo,    -   (d) hydroxy,    -   (e) trifluoromethyl,    -   (f) —OCF₃;    -   (g) —CO₂—C₁₋₆alkyl,    -   (h) —NH₂,    -   (i) —NH—C₁₋₆alkyl,    -   (j) —CONH₂, and    -   (k) —CONH—C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R³ isphenyl, which is unsubstituted or substituted with hydroxy, halo,—CONHC₁₋₆alkyl or —CO₂C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R³ ispyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, furanyl orthienyl.

An embodiment of the present invention includes compounds wherein R³ ispyridyl.

An embodiment of the present invention includes compounds wherein R³ ispyrimidinyl.

An embodiment of the present invention includes compounds wherein R⁴ andR⁵ are joined together to form a phthalimidyl ring.

An embodiment of the present invention includes compounds wherein R⁵ ishydrogen or C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R⁶ ishydrogen.

An embodiment of the present invention includes compounds wherein n is1.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the title compounds of theExamples herein and pharmaceutically acceptable salts thereof.

The compounds of the present invention are allosteric modulators ofmetabotropic glutamate (mGluR) receptor function, in particular they areallosteric modulators of mGluR5 receptors. Allosteric modulation can bepositive or negative. Positive allosteric modulators are referred to as“potentiators,” and negative allosteric modulators are referred to as“noncompetitive antagonists.” The term “potentiator” refers to acompound that increases or augments agonist activity, but which does notitself activate the receptor. That is, the compounds of the presentinvention do not appear to bind at the glutamate recognition site on themGluR receptor, but in the presence of glutamate or a glutamate agonist,the compounds of the present invention increase mGluR receptor response.The present potentiators are expected to have their effect at mGluRreceptors by virtue of their ability to increase the response of suchreceptors to glutamate or glutamate agonists, enhancing the function ofthe receptors. It is recognized that the potentiators of the presentinvention would be expected to increase the effectiveness of glutamateand glutamate agonists of the mGluR5 receptor. The presentnoncompetitive antagonists are expected to have their effect at mGluRreceptors by virtue of their ability to decrease the response of suchreceptors to glutamate or glutamate agonists, reducing the function ofthe receptors. It is recognized that the noncompetitive antagonists ofthe present invention would be expected to decrease the effectiveness ofglutamate and glutamate agonists of the mGluR5 receptor. Thus, thepotentiators or noncompetitive antagonists of the present invention areexpected to be useful in the treatment of various neurological andpsychiatric disorders associated with glutamate dysfunction described tobe treated herein and others that can be treated by such potentiators asare appreciated by those skilled in the art.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without preferredstereochemistry.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereomeric mixture, followed by separation of the individualdiastereomers by standard methods, such as fractional crystallization orchromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaamine,tripropylamine, tromethaamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will beunderstood that, as used herein, references to the compounds of FormulaI are meant to also include the pharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The subject compounds are useful in a method of potentiatingmetabotropic glutamate receptor activity in a patient such as a mammalin need of such potentiation comprising the administration of aneffective amount of the compound. The present invention is directed tothe use of the compounds disclosed herein as potentiators ofmetabotropic glutamate receptor activity. In addition to primates,especially humans, a variety of other mammals can be treated accordingto the method of the present invention.

In a like manner, the subject noncompetitive antagonist compounds areuseful in a method of inhibiting metabotropic glutamate receptoractivity in a patient such as a mammal in need of such inhibitioncomprising the administration of an effective amount of the compound.The present invention is directed to the use of the compounds disclosedherein as noncompetitive antagonists of metabotropic glutamate receptoractivity. In addition to primates, especially humans, a variety of othermammals can be treated according to the method of the present invention.

The present invention is further directed to a method for themanufacture of a medicament for potentiating or inhibiting metabotropicglutamate receptor activity in humans and animals comprising combining acompound of the present invention with a pharmaceutical carrier ordiluent.

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom potentiation orinhibition of metabotorpic glutamate receptor activity is desired. Theterm “therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. It is recognized thatone skilled in the art may affect the neurological and psychiatricdisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient afflicted with such disorderswith an effective amount of the compound of the present invention. Asused herein, the terms “treatment” and “treating” refer to all processeswherein there may be a slowing, interrupting, arresting, controlling, orstopping of the progression of the neurological and psychiatricdisorders described herein, but does not necessarily indicate a totalelimination of all disorder symptoms, as well as the prophylactictherapy of the mentioned conditions, particularly in a patient who ispredisposed to such disease or disorder.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual in need of treatment.

The utility of the compounds in accordance with the present invention aspotentiators or noncompetitive antagonists of metabotropic glutamatereceptor activity, in particular mGluR5 activity, may be demonstrated bymethodology known in the art. Chinese Hamster Ovary cells transfectedwith human or rat mGluR5 were plated in clear bottomed assay plates forassay in a Fluorometric Plate Reader (FLIPR). The cells were loaded witha Ca²⁺-sensitive fluorescent dye (e.g. Fluo-4), and the plates werewashed and placed in the FLIPR instrument. After establishment of afluorescence baseline for 10 seconds, the compounds in the presentinvention were added to the cells, and the response of the cells wasmeasured. Five minutes later, an mGluR5 agonist (e.g, glutamate,3,5-dihydroxyphenylglycine, or quisqualate) was added to the cells, andthe response of the cells was measured. Potentiation of the agonistresponse of mGluR5 by the compounds in the present invention wasobserved as an increase in response to non-maximal concentrations ofagonist in the presence of compound compared to the response to agonistin the absence of compound. In a like manner, antagonism of the agonistresponse of mGluR5 by the compounds in the present invention wasobserved as a decrease in response to non-maximal concentrations ofagonist in the presence of compound compared to the response to agonistin the absence of compound.

The assay described above was performed in two modalities. In the first,a range of concentrations of the present compound was added to thecells, followed by a single fixed concentration of agonist. If thecompound acted as a potentiator, an EC₅₀ value for potentiation and amaximum extent of potentiation by the compound at this concentration ofagonist was determined by non-linear curve fitting. If the compoundacted as a noncompetitive antagonist, an IC50 value was determined bynonlinear curve fitting. In the second modality, several fixedconcentrations of the present compound was added to the various wells onthe plate, followed by a range of concentrations of agonist for eachconcentration of present compound. The EC₅₀ values for the agonist ateach concentration of compound were determined by non-linear curvefitting. A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compound (a leftward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5potentiation at a given concentration of the present compound. Anincrease in the agonist EC₅₀ value with increasing concentrations of thepresent compound (a rightward shift of the agonistconcentration-response curve) is an indication of the degree of mGluR5antagonism at a given concentration of the present compound. This lattermodality also demonstrates whether the present compound also affects themaximum response of mGluR5 to agonists.

In particular, the compounds of the following examples had activity inpotentiating or inhibiting the mGluR5 receptor in the aforementionedassays, generally with an EC₅₀ for potentiation or an IC₅₀ forinhibition of less than about 10 μM. Preferred compounds within thepresent invention had activity in potentiating or inhibiting the mGluR5receptor in the aforementioned assays with an EC₅₀ for potentiation oran IC₅₀ for inhibition of less than about 1 μM. Preferred compoundscaused a change (increase or decrease) in agonist EC₅₀ value of greaterthan about three-fold. These compounds did not cause mGluR5 to respondin the absence of agonist, and they did not cause a significant increasein the maximal response of the mGluR5 to agonists, although thenoncompetitive antagonists did cause a decrease in maximal response toagonists. These compounds acted at potentiators or noncompetitiveantagonists of rat mGluR5 as well as human mGluR5. These compounds wereselective for mGluR5 compared with other metabotropic glutamatereceptors. Such a result is indicative of the intrinsic activity of thecompounds in use as potentiators or noncompetitive antagonists of mGluR5receptor activity.

Metabotropic glutamate receptors including the mGluR5 receptor have beenimplicated in a wide range of biological functions. This has suggested apotential role for these receptors in a variety of disease processes inhumans or other species.

The compounds of the present invention have utility in treating,preventing, ameliorating, controlling or reducing the risk of a varietyof neurological and psychiatric disorders associated with glutamatedysfunction, including one or more of the following conditions ordiseases: acute and chronic neurological and psychiatric disorders suchas cerebral deficits subsequent to cardiac bypass surgery and grafting,stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatalhypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia(including AIDS-induced dementia), Alzheimer's disease, Huntington'sChorea, amyotrophic lateral sclerosis, ocular damage, retinopathy,cognitive disorders, idiopathic and drug-induced Parkinson's disease,muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, migraine (including migraineheadache), urinary incontinence, substance tolerance, addictivebehavior, including addiction to substances (including opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.), withdrawal from such addictive substances(including substances such as opiates, nicotine, tobacco products,alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), obesity,psychosis, schizophrenia, anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder), mooddisorders (including depression, mania, bipolar disorders), trigeminalneuralgia, hearing loss, tinnitus, macular degeneration of the eye,emesis, brain edema, pain (including acute and chronic pain states,severe pain, intractable pain, neuropathic pain, and post-traumaticpain), tardive dyskinesia, sleep disorders (including narcolepsy),attention deficit/hyperactivity disorder, and conduct disorder.

Of the disorders above, the treatment of cognitive disorders, anxiety,schizophrenia or psychosis, Parkinson's disease, obesity and addictivebehaviors are of particular importance. In a preferred embodiment thepresent invention provides a method for preventing or treating cognitivedisorders, comprising: administering to a patient in need thereof aneffective amount of a compound of formula I. In another preferredembodiment the present invention provides a method for preventing ortreating anxiety, comprising: administering to a patient in need thereofan effective amount of a compound of formula I. Particularly preferredanxiety disorders are generalized anxiety disorder, panic disorder, andobsessive compulsive disorder. In another preferred embodiment thepresent invention provides a method for treating schizophrenia orpsychosis, comprising: administering to a patient in need thereof aneffective amount of a compound of formula I. In another preferredembodiment the present invention provides a method for treatingParkinson's disease, comprising: administering to a patient in needthereof an effective amount of a compound of formula I. In anotherpreferred embodiment the present invention provides a method forpreventing or treating obesity, comprising: administering to a patientin need thereof an effective amount of a compound of formula I. In yetanother preferred embodiment the present invention provides a method fortreating addictive behaviors, comprising: administering to a patient inneed thereof an effective amount of a compound of formula I.Particularly preferred addictive behaviors are addiction to substances(including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

Of the neurological and psychiatric disorders associated with glutamatedysfunction which are treated according to the present invention, thetreatment of s cognitive disorders, anxiety, schizophrenia or psychosis,Parkinson's disease, obesity and addictive behaviors are particularlypreferred. Particularly preferred anxiety disorders are generalizedanxiety disorder, panic disorder, and obsessive compulsive disorder.Particularly preferred addictive behaviors are addiction to substances(including opiates, nicotine, tobacco products, alcohol,benzodiazepines, cocaine, sedatives, hypnotics, etc.), withdrawal fromsuch addictive substances (including substances such as opiates,nicotine, tobacco products, alcohol, benzodiazepines, cocaine,sedatives, hypnotics, etc.) and substance tolerance.

In another preferred embodiment the present invention provides a methodfor treating schizophrenia, comprising: administering to a patient inneed thereof an effective amount of a compound of formula I or apharmaceutical composition thereof. At present, the fourth edition ofthe Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)(1994, American Psychiatric Association, Washington, D.C.), provides adiagnostic tool including schizophrenia and related disorders.

As used herein the term “schizophrenia” includes treatment of thosepsychotic disorders and related disorders as described in the DSM-IV.The skilled artisan will recognize that there are alternativenomenclatures, nosologies, and classification systems for neurologicaland psychiatric disorders, and particular schizophrenia, and that thesesystems-evolve with medical scientific progress. Thus, the term“schizophrenia” is intended to include like disorders that are describedin other diagnostic sources.

In another preferred embodiment the present invention provides a methodfor treating anxiety, comprising: administering to a patient in needthereof an effective amount of a compound of formula I or apharmaceutical composition thereof. At present, the fourth edition ofthe Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)(1994, American Psychiatric Association, Washington, D.C.), provides adiagnostic tool including anxiety and related disorders. These include:panic disorder with or without agoraphobia, agoraphobia without historyof panic disorder, specific phobia, social phobia, obsessive-compulsivedisorder, post-traumatic stress disorder, acute stress disorder,generalized anxiety disorder, anxiety disorder due to a general medicalcondition, substance-induced anxiety disorder and anxiety disorder nototherwise specified. As used herein the term “anxiety” includestreatment of those anxiety disorders and related disorder as describedin the DSM-IV. The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders, and particular anxiety, and thatthese systems evolve with medical scientific progress. Thus, the term“anxiety” is intended to include like disorders that are described inother diagnostic sources.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reducation of risk of the diseases,disorders and conditions noted herein.

The subject compounds are further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions in combination withother agents, including an mGluR agonist.

The term “potentiated amount” refers to an amount of an mGluR agonist,that is, the dosage of agonist which is effective in treating theneurological and psychiatric disorders described herein whenadministered in combination with an effective amount of a potentiatorcompound of the present invention. A potentiated amount is expected tobe less than the amount that is required to provided the same effectwhen the mGluR agonist is administered without an effective amount of apotentiator compound of the present invention.

A potentiated amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining a potentiated amount, the dose of an mGluRagonist to be administered in combination with a compound of formula I,a number of factors are considered by the attending diagnostician,including, but not limited to: the mGluR agonist selected to beadministered, including its potency and selectivity; the compound offormula I to be coadministered; the species of mammal; its size, age,and general health; the specific disorder involved; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the modes of administration; the bioavailabilitycharacteristics of the preparations administered; the dose regimensselected; the use of other concomitant medication; and other relevantcircumstances.

A potentiated amount of an mGluR agonist to be administered incombination with an effective amount of a compound of formula I isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day and is expected to be lessthan the amount that is required to provided the same effect whenadministered without an effective amount of a compound of formula I.Preferred amounts of a co-administered mGlu agonist are able to bedetermined by one skilled in the art.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of Formula I or the other drugs may have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. Such other drug(s) may be administered, by a routeand in an amount commonly used therefor, contemporaneously orsequentially with a compound of Formula I. When a compound of Formula Iis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompound of Formula I is preferred. However, the combination therapy mayalso includes therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compounds of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used.

In such combinations the compound of the present invention and otheractive agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. In addition to thetreatment of warm-blooded animals such as mice, rats, horses, cattle,sheep, dogs, cats, monkeys, etc., the compounds of the invention areeffective for use in humans.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethylene-oxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of The present invention are employed.(For purposes of this application, topical application shall includemouth washes and gargles.)

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require potentiation of metabotorpic glutamatereceptor activity an appropriate dosage level will generally be about0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0,20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day.

When treating, preventing, controlling, ameliorating, or reducing therisk of neurological and psychiatric disorders associated with glutamatedysfunction or other diseases for which compounds of the presentinvention are indicated, generally satisfactory results are obtainedwhen the compounds of the present invention are administered at a dailydosage of from about 0.1 milligram to about 100 milligram per kilogramof animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 milligramsto about 1000 milligrams, preferably from about 1 milligrams to about 50milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 7 milligrams to about 350 milligrams. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

CH₂Cl₂ dichloromethane DIEA diisopropylethylamine DMFN,N-dimethylformamide CCl₄ carbon tetrachloride Bz₂O₂ benzoylperoxideNBS N-bromosuccinamide PS-DIEA polystyrene diisopropylethylamine PS-DMAPpolystyrene 4-N,N-dimethylaminopyridine THF tetrahydrofuran TFAtrifluoroacteic acid MeOH methanol Ra—Ni Raney Nickel.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsand the requisite intermediates are in some cases commerciallyavailable, or can be prepared according to literature procedures or asillustrated herein.

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. Substituent numbering as shown in the schemesdoes not necessarily correlate to that used in the claims and often, forclarity, a single substituent is shown attached to the compound wheremultiple substituents are allowed under the definitions hereinabove.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the Reaction Schemes I-IV, inaddition to other standard manipulations such as ester hydrolysis,cleavage of protecting groups, etc., as may be known in the literatureor exemplified in the experimental procedures.

These reactions may be employed in a linear sequence to provide thecompounds of the invention or they may be used to synthesize fragmentswhich are subsequently joined by the alkylation reactions described inthe Reaction Schemes.

In some cases the final product may be further modified, for example, bymanipulation of substituents. These manipulations may include, but arenot limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart. In some cases the order of carrying out the foregoing reactionschemes may be varied to facilitate the reaction or to avoid unwantedreaction products. The following examples are provided so that theinvention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way.

As illustrated in Reaction Scheme I, a suitably substituted othro-methylaniline I-1 is acylated under standard conditions to provide thecorresponding amide I-2. Intermediate I-2 may then be subjected to astandard bromination reaction to deliver benzylic bromide I-3.Intermediate I-3 may then be subjected to nucleophilic displacement ofthe benzylic bromide with a variety of nitrogen nucleophiles to producebenzamide instant compounds, I-4.

Reaction Scheme II illustrates the preparation of the compounds of thisinstant invention, starting from a suitably substituted ortho-cyanoaniline II-1, that can be acylated under standard conditions to produceII-2. Intermediate II-2 may be reduced by a heterogeneous nickelcatalyst under a hydrogen atmosphere to deliver the correspondingbenzylic amine II-3. Reaction with a suitably substituted 1,2-diacidhalide delivers the corresponding phthalido-benzamide instant compounds,II-4.

Reaction Scheme III illustrates the preparation of the compounds of thisinstant invention, starting from intermediate II-3. Acylation understandard conditions provides benzamide instant compounds, III-1.

Reaction Scheme IV illustrates the preparation of the compounds of thisinstant invention, starting from intermediate II-3. Nucleophilicdisplacement of the benzylic bromide with functionalized primiary amines(H₂NR⁵) delivers the corresponding benzylic amine IV-1. Acylation understandard conditions provides the benzamide instant compounds, IV-1.

In some cases the order of carrying out the foregoing reaction schemesmay be varied to facilitate the reaction or to avoid unwanted reactionproducts. The following examples are provided so that the inventionmight be more fully understood. These examples are illustrative only andshould not be construed as limiting the invention in any way. Particularmaterials employed, species and conditions are intended to be furtherillustrative of the invention and not limitative of the reasonable scopethereof.

2-{[(4-chloro-2-methylphenyl)amino]carbonyl}phenyl acetate (1-2)

To a stirred solution of 4-chloro-2-methylaniline, 1-1, (10.0 g 0.071moles) in toluene was added (24.7 mL 0.014 moles) ofN,N-diisopropylethylamine, followed by slow addition of acetylsalicyloylchloride. The mixture was stirred until complete by TLC. Reaction wasfiltered and dried under vacuum to afford 9.4 grams of 1-2. AnalyticalLCMS: (CH₃CN/H₂O/1% TFA, 4 min gradient), 88% pure, M+1 peak m/e 304.

2-({[2-(bromomethyl)-4-chlorophenyl]amino}carbonyl)phenyl acetate (1-3)

1-2 (9.4 g 0.031 moles) was immediately taken up in a solution of CCl₄with recrystallized N-Bromosuccinimide (5.5 g 0.031 moles) and benzoylperoxide (0.75 g 3.10 mmoles). The reaction was heated at 90 degreescelsius, along with a light source, until complete by TLC. Uponcompletion, the solvent was reduced by two-thirds and filtered through asmall plug of silica gel yielding 10.5 grams of 1-3. Analytical LCMS:(CH₃CN/H₂O/1% TFA, 4 min gradient), 85% pure, M+1 peak m/e 384.

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide(1-4)

Compound 1-3 (6.0 g 0.015 moles) was dissolved in 50 mL of DMF. To thatpthalimide (3.31 g 0.023 moles), K₂CO₃ (6.2 g 0.045 moles) and acatalytic amount of KI were added and allowed to stir at 50° C.overnight. Upon completion the reaction was diluted with ethyl acetateand then washed with brine (6×25 mL's) to afford 2.9 grams of 1-4 in acrude mixture, which was then purified by normal phase chromatography.¹H NMR (300 MHz, CDCl₃): 4.83 ppm (2H, S); 7.05 ppm (2H, m); 7.36 ppm(1H, dd, J=2.4 Hz, 8.6 Hz); 7.50 ppm (1H, dt, J=1.5 Hz, 8.5 Hz); 7.59ppm (1H, d, J=2.4 Hz); 7.75 ppm (3H, m); 7.91 ppm (2H, m); 8.18 ppm (1H,d, 7.2 Hz); 10.17 ppm (1H, s); 12.27 ppm (1H,s) Analytical LCMS: singlepeak (214 nm) at 3.633 min (CH₃CN/H₂O/1% TFA, 4 min gradient), HRMScalc'd for C₂₂H₁₅N₂O₄Cl (M+H), 407.0799; found 407.0793 (M+H).

Compounds in Table 1 were synthesized as shown in Scheme 1, butsubstituting the appropriately substituted nitrogen nucleophile forphthalimide in Scheme 1, or the appropriatley substituted nitrogennucleophile or 1,2-diacid chloride in Reaction Schemes 1 and 2. Therequisite were commercialy available, described in the literature orreadily synthesized by one skilled in the art of organic synthesis.

TABLE 1 MS Compound Nomenclature M + 1

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide392.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyrimidine-2-carboxamide393.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide407.8

2-[({2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}amino)-carbonyl]phenylacetate 433.4

N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}-2-hydroxybenzamide391.4

2-chloro-N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methy]-3-fluorophenyl}benzamide409.8

N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}-2-fluorobenzamide393.4

N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}benzamide375.3

N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}-3,5-difluorobenzamide411.3

N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide358.4

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methoxybenzamide421.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-methylbenzamide405.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-furamide381.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-5-methylisoxazole-3-carboxamide396.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}cyclo-hexanecarboxamide397.8

N-{5-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}cyclo-hexanecarboxamide397.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-1-methyl-1H-imidazole-2-carboxamide395.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-1,3-thiazole-4-carboxamide398.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-hydroxypyridine-2-carboxamide408.8

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}imid-azo[2,1-b][1,3]thiazole-6-carboxamide437.9

N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-1,2,5-thiadiazole-3-carboxamide399.8

N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methoxyphenyl}pyridine-2-carboxamide388.4

N-{4-bromo-2-[(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide455.3

N-{4-chloro-2-[(2,5-dioxo-3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]-phenyl}pyridine-2-carboxamide418.9

N-{4-chloro-2-[(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide410.8

N-{4-chloro-2-[(5,6-dimethyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide420.8

N-{4-chloro-2-[(5-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide410.8

N-{4-chloro-2-[(5-ethoxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide436.9

N-{5-bromo-3-[(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]pyridin-2-yl}pyridine-2-carboxamide507.1

N-{4-chloro-2-[(5-hydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide408.8

N-{4-bromo-2-[(5-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide455.2

N-{4-bromo-2-[(5-ethoxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide481.3

N-{4-bromo-2-[(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide506.1

N-{4-bromo-2-[(4,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide506.1

N-{2-[(4,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-fluorophenyl}pyridine-2-carboxamide445.2

N-{2-[(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-fluorophenyl}pyridine-2-carboxamide445.2

N-{4-fluoro-2-[(5-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-phenyl}pyridine-2-carboxamide421.4

N-{4-bromo-2-[(4-methyl-1,3-dioxo-3,4,5,6-tetrahydrocyclo-penta[c]pyrrol-2(1H)-yl)methyl]-phenyl}pyridine-2-carboxamide441.3

N-(4-bromo-2-cyanophenyl)pyridine-2-carboxamide (2-2)

To a stirred solution of 2-amino-5-bromobenzonitrile 2-1 (2.8 g, 0.014moles) in toluene was added (4.95 mL, 0.028 moles) ofN,N-diisopropylethylamine, followed by slow addition of (2.74 g, 0.015moles) picolinoyl chloride. The mixture was stirred until complete byTLC. Reaction was filtered and dried under vacuum to afford 3 grams of2-2. Analytical LCMS: (CH₃CN/H₂O/1% TFA, 4 min gradient), 95% pure, M+1peak m/e 301.

N-[2-(aminomethyl)-4-bromophenyl]pyridine-2-carboxamide (2-3)

2-2 (3 g, 0.0099 moles) was immediately taken up in a solution of 2.0Mammonia in methanol. To this solution was added catalytic Raney nickel.The reaction was stirred with a hydrogen balloon attached until completeby TLC. Upon completion, the reaction was filtered and the solvent wasremoved yielding 2.9 grams of 2-3. Analytical LCMS: (CH₃CN/H₂O/1% TFA, 4min gradient), 95% pure, M+1 peak m/e 306.

N-{5-bromo-2-[(pyridin-2-ylcarbonyl)amino]benzyl}pyridine-2-carboxamide(2-4)

Compound 2-3 (0.050 g, 0.16 mmoles) was dissolved in 6 mL of methylenechloride. To the reaction vessel was added (0.06 mL, 0.32 mmoles) ofN,N-diisopropylethylamine and (200 mg, 0.32 mmols, 1.49 mmol/gram)followed by the addition of (0.057 g, 0.32 mmol) picolinoyl chloride.The mixture was stirred until complete by TLC. The compound was thenfiltered and then the solvent was removed and then purified on a massguided LC/MS to provide 46 mg (70%) of the title compound. ¹H NMR (300MHz, CDCl₃): 8.89 ppm (s, 2H), 8.43 ppm (m, 2H), 8.22 ppm (m, 2H), 8.13ppm (t, J=4 Hz, 1H), 8.0 ppm (s, 1H), 7.81 ppm (m, 2H), 7.41 ppm (m,1H), 7.2 ppm (m, 2H), 4.22 ppm (d, J=4 Hz, 2H); HRMS calc'd forC₁₉H₁₅BrN₄O₂ (M+1) 411.0451; Found: 411.0444

Compounds in Table 2 were synthesized as shown in Scheme 2, butsubstituting the appropriately substituted acid chloride for picolinoylchloride in Scheme 2, or the appropriatley substituted acid chloride inReaction Scheme 3 or by the appropriatley substituted primary amine(R⁷NH₂) and acid chloride in Reaction Scheme 4. The requisite werecommercialy available, described in the literature or readilysynthesized by one skilled in the art of organic synthesis.

TABLE 2 MS Compound Nomenclature M + 1

N-(4-bromo-2-{[(2-fluorobenzoyl)amino]-methyl}phenyl)pyridine-2-carboxamide429.3

N-{5-bromo-2-[(pyridin-2-ylcarbonyl)amino]-benzyl}pyridine-2-carboxamide412.3

N-[4-bromo-2-({[2-(trifluoromethyl)benzoyl]-amino}methyl)-phenyl]pyridine-2-carboxamide479.3

N-(4-chloro-2-{[(3,5-dichlorobenzoyl)(ethyl)-amino]methyl}phenyl)-pyridine-2-carboxamide463.8

N-(2-{[(4-butoxybenzoyl)(ethyl)-amino]methyl}-4-chlorophenyl)pyridine-2-carboxamide467

N-(4-chloro-2-{[(3,5-dimethoxybenzoyl)(ethyl)-amino]methyl}phenyl)-pyridine-2-carboxamide454.9

N-(4-chloro-2-{[(3,4-dichlorobenzoyl)(ethyl)-amino]methyl}phenyl)-pyridine-2-carboxamide463.8

N-(4-chloro-2-{[(3,5-dichlorobenzoyl)(isobutyl)-amino]methyl}phenyl)-pyridine-2-carboxamide491.8

N-(4-chloro-2-{[(3,5-dimethoxybenzoyl)-(isobutyl)amino]methyl}-phenyl)pyridine-2-carboxamide483

N-{5-fluoro-2-[(pyridin-2-ylcarbonyl)amino]-benzyl}quinoxaline-2-carboxamide402.4

N-(2-{[(4-butoxybenzoyl)amino]-methyl}-4-fluorophenyl)pyridine-2-carboxamide422.5

N-(4-bromo-2-{[(3-methoxybenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide455.3

N-(4-chloro-2-{[(3,5-dichlorobenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide449.7

N-(2-{[[3,5-bis(trifluoromethyl)-benzoyl](methyl)amino]-methyl}-4-chlorophenyl)pyridine-2-carboxamide516.8

N-[4-chloro-2-({(3,5-dichlorobenzoyl)[2-(dimethylamino)ethyl]-amino}methyl)phenyl]-pyridine-2-carboxamide506.8

N-[2-(benzoylamino)-5-bromobenzyl]-N,3,5-trimethylbenzamide 452.4

N-(4-bromo-2-{[(3,5-dichlorobenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide494.2

N-(4-bromo-2-{[(3,4-difluorobenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide461.3

N-(4-bromo-2-{[(2,4-difluorobenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide461.3

N-(4-bromo-2-{[(3,4-dichlorobenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide494.2

N-[4-chloro-2-({methyl[2-(trifluoromethyl)-benzoyl]amino}methyl)-phenyl]pyridine-2-carboxamide448.2

N-(4-chloro-2-{[(3,4-dichlorobenzoyl)-(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide449.7

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.For example, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inresponsiveness of the mammal being treated for any of the indicationswith the compounds of the invention indicated above.

1. A compound of the formula I:

wherein: R¹ is selected from the group consisting of: (1) hydrogen, (2)halogen, (3) C₁₋₆alkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, (4) —OC₁₋₆alkyl, (5) —S(O)_(m)—C₁₋₆alkyl,wherein m is selected from 0, 1 and 2, (6) —CO₂R⁹, wherein R⁹ isindependently selected from: (a) hydrogen, (b) —C₁₋₆alkyl, which isunsubstituted or substituted with 1-6 fluoro, (c) benzyl, and (d)phenyl, (7) —NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ are independently selectedfrom: (a) hydrogen, (b) —C₁₋₆alkyl, which is unsubstituted orsubstituted with 1-6 fluoro, (c) —C₅₋₆cycloalkyl, (d) benzyl, (e)phenyl, (f) —S(O)₂—C₁₋₆alkyl, (g) —S(O)₂-benzyl, and (h) —S(O)₂-phenyl,(8) —S(O)₂—NR¹⁰R¹¹, (9) phenyl, which is unsubstituted or substitutedwith one or more substituents independently selected from: (a)—C₁₋₆alkyl, (b) —O—C₁₋₆alkyl, (c) halo, (d) hydroxy, (e)trifluoromethyl, and (f) —OCF₃; R³ is selected from the group consistingof: (1) C₁₋₆alkyl, which is substituted with halogen, hydroxyl orphenyl, (2) C₃₋₇cycloalkyl, which is unsubstituted or substituted withhalogen, hydroxyl or phenyl, and (3) phenyl, which is unsubstituted orsubstituted with one or more substituents independently selected from:(a) —C₁₋₆alkyl, which is unsubstituted or substituted with —NR¹⁰R¹¹, (b)—O—C₁₋₆alkyl, (c) halo, (d) hydroxy, (e) trifluoromethyl, (f) —OCF₃; (g)—CO₂R⁹, (h) —NR¹⁰R¹¹, (i) —C(O)NR¹⁰R¹¹, and (j) —NO₂, (4) heterocycle,wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl,benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, which is unsubstituted or substituted with one or moresubstituents independently selected from: (a) —C₁₋₆alkyl, (b)—O—C₁₋₆alkyl, (c) halo, (d) hydroxy, (e) phenyl, (f) trifluoromethyl,(g) —OCF₃; (h) —CO₂R⁹, (i) —NR¹⁰R¹¹, and (j) —CONR¹⁰R¹¹; R⁴ is selectedfrom the group consisting of: (1) C₁₋₆alkyl, which is unsubstituted orsubstituted with halogen, hydroxyl or phenyl, (2) C₃₋₇cycloalkyl, whichis unsubstituted or substituted with halogen, hydroxyl or phenyl, and(3) phenyl, which is unsubstituted or substituted with one or moresubstituents independently selected from: (a) —C₁₋₆alkyl, (b)—O—C₁₋₆alkyl, (c) halo, (d) hydroxy, (e) trifluoromethyl, (f) —OCF₃, (g)—CO₂R⁹, (h) —NR¹⁰R¹¹, (i) —CONR¹⁰R¹¹, and (j) —NO₂; (4) heterocycle,wherein heterocycle is selected from: benzoimidazolyl, benzimidazolonyl,benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl,benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl,furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl,isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline,oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl,thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, which is unsubstituted or substituted with one or moresubstituents independently selected from: (a) —C₁₋₆alkyl, (b)—O—C₁₋₆alkyl, (c) halo, (d) hydroxy, (e) phenyl, (f) trifluoromethyl,(g) —OCF₃, (h) —CO₂R⁹, (i) —NR¹⁰R¹¹, and (j) —CONR¹⁰R¹¹; or wherein R⁴and R⁵ are joined together to form a phthalimidyl, succinimidyl orglutamidyl ring, which is unsubstituted or substituted with one or moresubstituents independently selected from the definitions of R²; R² isselected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3)—O—C₁₋₆alkyl, (4) halo, (5) hydroxyl, (6) —NO₂, and (7) phenyl; R⁵ andR⁶ are independently selected from the group consisting of: (1)hydrogen, and (2) C₁₋₆alkyl; n is an integer selected from 1, 2 and 3;with the proviso that the compound of formula I is not:N-[4-chloro-2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]phenyl]-acetamide, N-[2-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)methyl]-4-methylphenyl]-acetamide, orN-[2-[(1,3-dihydro- 1,3-dioxo-2H-isoindol-2-yl)methyl]phenyl]-acetamide;or a pharmaceutically acceptable salt thereof.
 2. The compound of claim1 of the formula Ia:

wherein R² is selected from the group consisting of: (1) hydrogen, (2)—C₁₋₆alkyl, (3) —O—C₁₋₆alkyl, (4) halo, (5) hydroxy, (6) —NO₂, and (7)phenyl; or a pharmaceutically acceptable salt thereof.
 3. The compoundof claim 1 of the formula Ib:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1 of the formula Ic:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1 of the formula Id:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1 of the formula Ie:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 of the formula If:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1 wherein R¹ is hydrogen.
 9. The compound of claim 1 wherein R² is halo.10. The compound of claim 9 wherein R² is fluoro.
 11. The compound ofclaim 9 wherein R² is chloro.
 12. The compound of claim 9 wherein R² isbromo.
 13. The compound of claim 1 wherein R² is methyl.
 14. Thecompound of claim 1 wherein R³ is phenyl, which is unsubstituted orsubstituted with one or more substituents independently selected from:(a) —C₁₋₆alkyl, (b) —O—C₁₋₆alkyl, (c) halo, (d) hydroxy, (e)trifluoromethyl, (f) —OCF₃; (g) —CO₂—C₁₋₆alkyl, (h) —NH₂, (i)—NH—C₁₋₆alkyl, (j) —CONH₂, and (k) —CONH—C₁₋₆alkyl.
 15. The compound ofclaim 14 wherein R³ is phenyl, which is unsubstituted or substitutedwith hydroxy, halo, —CONHC₁₋₆alkyl or —CO₂C₁₋₆alkyl.
 16. The compound ofclaim 1 wherein R³ is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,piperazinyl, furanyl or thienyl.
 17. The compound of claim 1 wherein R⁴and R⁵ are joined together to form a phthalimidyl ring.
 18. The compoundof claim 1 wherein R⁵ is hydrogen or C₁₋₆alkyl.
 19. The compound ofclaim 1 wherein R⁶ is hydrogen.
 20. The compound of claim 1 wherein nis
 1. 21. A compound which is selected from the group consisting of:N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyrimidine-2-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide;2-[({2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}amino)carbonyl]phenyl;N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}-2-hydroxybenzamide;2-chloro-N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}benzamide;N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}-2-fluorobenzamide;N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}benzamide;N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3-fluorophenyl}-3,5-difluorobenzamide;N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-methoxybenzamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-methylbenzamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-furamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-5-methylisoxazole-3-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}cyclohexanecarboxamide;N-{5-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}cyclohexanecarboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-1-methyl-1H-imidazole-2-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-1,3-thiazole-4-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-3-hydroxypyridine-2-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}imidazo[2,1-b][1,3]thiazole-6-carboxamide;N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-1,2,5-thiadiazole-3-carboxamide;N-{2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-methoxyphenyl}pyridine-2-carboxamide;N-{4-bromo-2-[(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(2,5-dioxo-3-phenyl-2,5-dihydro-1H-pyrrol-1-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(5,6-dimethyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(5-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-chloro-2-[(5-ethoxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{5-bromo-3-[(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]pyridin-2-yl}pyridine-2-carboxamide;N-{4-chloro-2-[(5-hydroxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-bromo-2-[(5-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-bromo-2-[(5-ethoxy-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-bromo-2-[(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-bromo-2-[(4,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{2-[(4,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-fluorophenyl}pyridine-2-carboxamide;N-{2-[(5,6-dichloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-fluorophenyl}pyridine-2-carboxamide;N-{4-fluoro-2-[(5-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}pyridine-2-carboxamide;N-{4-bromo-2-[(4-methyl-1,3-dioxo-3,4,5,6-tetrahydrocyclopenta[c]-pyrrol-2(1H)-yl)methyl]phenyl}pyridine-2-carboxamide;N-{5-bromo-2-[(pyridin-2-ylcarbonyl)amino]benzyl}pyridine-2-carboxamide;N-(4-bromo-2-{[(2-fluorobenzoyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-{5-bromo-2-[(pyridin-2-ylcarbonyl)amino]benzyl}pyridine-2-carboxamide;N-[4-bromo-2-({[2-(trifluoromethyl)benzoyl]amino}methyl)phenyl]-pyridine-2-carboxamide;N-(4-chloro-2-{[(3,5-dichlorobenzoyl)(ethyl)amino]methyl}phenyl)-pyridine-2-carboxamide;N-(2-{[(4-butoxybenzoyl)(ethyl)amino]methyl}-4-chlorophenyl)-pyridine-2-carboxamide;N-(4-chloro-2-{[(3,5-dimethoxybenzoyl)(ethyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-(4-chloro-2-{[(3,4-dichlorobenzoyl)(ethyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-(4-chloro-2-{[(3,5-dichlorobenzoyl)(isobutyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-(4-chloro-2-{[(3,5-dimethoxybenzoyl)(isobutyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-{5-fluoro-2-[(pyridin-2-ylcarbonyl)amino]benzyl}quinoxaline-2-carboxamide;N-(2-{[(4-butoxybenzoyl)amino]methyl}-4-fluorophenyl)pyridine-2-carboxamide;N-(4-bromo-2-{[(3-methoxybenzoyl)(methyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-(4-chloro-2-{[(3,5-dichlorobenzoyl)(methyl)amino]methyl}phenyl)pyridine-2-carboxamide;N-(2-{[[3,5-bis(trifluoromethyl)benzoyl](methyl)amino]methyl}-4-chlorophenyl)pyridine-2-carboxamide;N-[4-chloro-2-({(3,5-dichlorobenzoyl)[2-(dimethylamino)ethyl]amino}methyl)-phenyl]pyridine-2-carboxamide;N-[2-(benzoylamino)-5-bromobenzyl]-N,3,5-trimethylbenzamide;N-(4-bromo-2-{[(3,5-dichlorobenzoyl)(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide;N-(4-bromo-2-{[(3,4-difluorobenzoyl)(methyl)amino]methyl}phenyl)-pyridine-2-carboxamide;N-(4-bromo-2-{[(2,4-difluorobenzoyl)(methyl)amino]methyl}phenyl)-pyridine-2-carboxamide;N-(4-bromo-2-{[(3,4-dichlorobenzoyl)(methyl)amino]methyl}phenyl)-pyridine-2-carboxamide;N-[4-chloro-2-({methyl[2-(trifluoromethyl)benzoyl]amino}methyl)-phenyl]pyridine-2-carboxamide;N-(4-chloro-2-{[(3,4-dichlorobenzoyl)(methyl)amino]methyl}-phenyl)pyridine-2-carboxamide;or a pharmaceutically acceptable salt thereof.
 22. A compound which is:

or a pharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition which comprises an insert carrier and a compound of claim 1or a pharmaceutically acceptable salt thereof.
 24. A pharmaceuticalcomposition which comprises an inert carrier and a compound of claim 21or a pharmaceutically acceptable salt thereof.
 25. A method forpotentiation or inhibition of metabotropic glutamate receptor activityin a mammal which comprises the administration of an effective amount ofthe compound of claim 1 or a pharmaceutically acceptable salt thereof.26. A method for treating, controlling, or reducing the risk ofschizophrenia in a mammalian patient in need of such which comprisesadministering to the patient a therapeutically effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt thereof.